Shear stress is a major determinant of blood vessel remodeling and function, and play an important role in atherogenesis as atherosclerotic plaque forms exclusively in regions where flow departs from the laminar mode and become turbulent, independent of other risk factors. Despite its clinical and physiological significance, the mechanisms by which endothelial cells sense shear stress are poorly understood. Published and preliminary data suggest that both integrins and the Rho family GTPases Rho, Rac and Cdc42 participate in sensation of shear stress. Additional data indicate that integrins can regulate activity of Rho family GTPases. We ther3efore propose to test the hypothesis that integrins and Rho family GTPases mediate cellular responses to shear stress. These experiments will be accomplished using novel assays recently developed in my laboratory. 2) To investigate the roles of specific integrins and ligands in mediating cellular responses to mechanical stimuli. These experiments will define the integrin specificity of shear-induced events. 3) To determine whether Rho, Rac or Cdc42 are required for cellular responses to shear The effects of inhibitors of these pathways on shear responses will be tested to determine whether GTPases are necessary for cellular responses to shear. In some cases, activators of Rho, Rac or Cdc42 will be tested to determine if GTPase activation is sufficient to elicit the response. These experiments will define the roles of integrins and Rho family GTPases in cellular responses to shear, and may lead to the development of novel therapeutics that target these pathways to treat or prevent atherosclerosis.